Resistance to pyrethroids, the sole insecticide class recommended for treating bed nets, threatens the control of major malaria vectors, including Anopheles funestus Effective management of resistance requires an understanding of the dynamics and mechanisms driving resistance. Here, using genome-wide transcription and genetic diversity analyses, we show that a shift in the molecular basis of pyrethroid resistance in southern African populations of this species is associated with a restricted gene flow. Across the most highly endemic and densely populated regions in Malawi, An. funestus is resistant to pyrethroids, carbamates, and organochlorides. Genome-wide microarray-based transcription analysis identified overexpression of cytochrome P450 genes as the main mechanism driving this resistance. The most up-regulated genes include cytochrome P450s (CYP) CYP6P9a, CYP6P9b and CYP6M7. However, a significant shift in the overexpression profile of these genes was detected across a south/north transect, with CYP6P9a and CYP6P9b more highly overexpressed in the southern resistance front and CYP6M7 predominant in the northern front. A genome-wide genetic structure analysis of southern African populations of An. funestus from Zambia, Malawi, and Mozambique revealed a restriction of gene flow between populations, in line with the geographical variation observed in the transcriptomic analysis. Genetic polymorphism analysis of the three key resistance genes, CYP6P9a, CYP6P9b, and CYP6M7, support barriers to gene flow that are shaping the underlying molecular basis of pyrethroid resistance across southern Africa. This barrier to gene flow is likely to impact the design and implementation of resistance management strategies in the region.

译文

对拟除虫菊酯的抗药性是推荐用于治疗蚊帐的唯一杀虫剂类别,它威胁到主要疟疾媒介的控制,包括对真菌按蚊的控制。有效管理抗药性需要了解驱动抗药性的动态和机制。在这里,使用全基因组转录和遗传多样性分析,我们表明该物种的南部非洲种群中拟除虫菊酯抗性分子基础的变化与基因流动受限有关。在马拉维最流行和人口稠密的地区,An。funestus对拟除虫菊酯,氨基甲酸酯和有机氯化物具有抗性。基于全基因组微阵列的转录分析确定了细胞色素P450基因的过表达是驱动这种抗性的主要机制。上调最多的基因包括细胞色素P450s (CYP) CYP6P9a、CYP6P9b和CYP6M7。然而,在南/北样带中检测到这些基因的过表达谱发生了显着变化,其中CYP6P9a和CYP6P9b在南部抵抗前沿更为高表达,而CYP6M7在北部前沿占主导地位。对来自赞比亚,马拉维和莫桑比克的南部非洲An. funestus种群的全基因组遗传结构分析显示,种群之间的基因流受到限制,这与转录组分析中观察到的地理变异一致。CYP6P9a,CYP6P9b和CYP6M7这三个关键抗性基因的遗传多态性分析支持了基因流障碍,这些障碍正在塑造整个南部非洲的拟除虫菊酯抗性的潜在分子基础。这种阻碍基因流的障碍可能会影响该地区抗性管理策略的设计和实施。

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